Intracellular acidification of human melanoma xenografts by the respiratory inhibitor m-iodobenzylguanidine plus hyperglycemia: A P-31 magnetic resonance spectroscopy study

In vivo P-31 magnetic resonance spectroscopy demonstrates that human melano ma xenografts can be significantly acidified by induction of hyperglycemia combined with administration of m-iodobenzylguanidine (MIBG), an inhibitor of mitochondrial respiration. In melanoma xenografts (less than or equal to 8 mm diameter), intracellular pH (pH(i), measured by the chemical shift of the P-i resonance) and extracellular pH (pH(c), measured with 3-aminopropy lphosphonate) was reduced by less than 0.2 unit during i.v. infusion of glu cose for 40 min, Administration of MIBG (30 mg/kg) under hyperglycemic cond itions (26 mM) reduced tumor pH(i) and pH(e) by similar to 0.4 (P < 0.001) and similar to 0.6 (P < 0.001) unit, respectively; coincidentally, the nucl eoside triphosphates:P-i ratio decreased similar to 60% (P < 0.001) relativ e to the baseline level. Minimal changes in pH(i) and pH(e) and a small dec rease in nucleoside triphosphates:P-i ratio (26%, P = 0.2) were observed in liver in response to MIBG plus hyperglycemia. These results suggest that u nder normoglycemic and hyperglycemic conditions, small human melanoma xenog rafts (18 mm) may exhibit a relatively high level of oxidative phosphorylat ion that mag be blocked by MIBG. The acidification may result from increase d lactate production as a direct effect of MIBG inhibition of respiration i n mitochondria of tumor cells, or through indirect systemic effects, which remain to be identified. The synergetic effects of MIBG and hyperglycemia r esult in significant acidification of the tumor and a decrease in tumor bio energetic status, and the effects are largely selective for tumors in compa rison with normal tissues.